Evidence that immune decline with age is function of oxidative stress

Free radicals (coupled with cells' decreased production of antioxidant enzymes) cause buildup of damaged proteins that can be toxic to immune cells

Researchers at Albert Einstein College of Medicine of Yeshiva University have uncovered one of the mechanisms by which aging may compromise the ability of the immune system to fight infections and respond to vaccines.

The study, conducted in aging mice, shows that administering antioxidants may help reverse this loss of immune function. (The findings were published online July 13 by Cell Reports.)

"Aging is known to affect immune function, a phenomenon known as immunosenescence, but how this happens is not clear," said study leader Laura Santambrogio, MD, PhD, associate professor of pathology and microbiology & immunology at Einstein. "Our study has uncovered several ways in which aging can worsen the body's overall ability to mount an effective immune response."

• All cells generate chemicals called free radicals as a normal part of metabolism.

• These highly reactive, unstable molecules can readily damage proteins, lipids and other cellular components through oxidation (the reaction between oxygen and substances it comes in contact with – as with rust formation on a tin can).

• Healthy cells keep "oxidative stress" in check by producing several enzymes that are scavengers of free radicals.

• But in aging, increased production of free radicals - coupled with cells' decreased production of antioxidant enzymes - causes a buildup of damaged proteins and other molecules that can be toxic to cells.

Protecting Dendritic Cells – the Immune Alarm System

The current study is the first to examine whether age-related oxidative stress compromises the function of a type of immune cell called dendritic cells.

"Dendritic cells are known as the 'sentinels of the immune system' and alert the rest of the immune system to the presence of microbial invaders," Dr. Santambrogio explains. "When you are exposed to viruses or bacteria, these cells engulf the pathogens and present them to the immune system, saying in effect, 'There's an infection going on, and here is the culprit - go get it.'"

Dr. Santambrogio and colleagues isolated dendritic cells from aging mice and found that oxidation-damaged proteins had accumulated in those cells and had caused harmful effects. For example, oxidatively modified proteins hampered the function of endosomes, the organelle on dentritic cells where pathogens are inactivated.

When the mice were injected with a potent antioxidant in the abdominal cavity daily for two weeks, some of the effects of oxidative stress were reversed.

This finding has implications for designing vaccines or therapies for humans, especially the elderly, whose weakened immune systems increase their susceptibility to infections and cancer, and reduce vaccine effectiveness.

"Many elderly people respond very poorly to vaccination, so perhaps a cycle of therapy with antioxidants before vaccination might improve their immune response to vaccines," Dr. Santambrogio notes.